The American soldier and adventurer James Wilkinson was born in Calvert County, Maryland, in 1757. At the outbreak of the American Revolution he abandoned the study of medicine to enter the Continental Army, and he served with General Benedict Arnold in the Quebec campaign and was later under General Horatio Gates, acting from May 1777 to March 1778 as adjutant-general of the Northern Department. He was sent to Congress to report Gates's success against Burgoyne, but his tardiness secured for him a sarcastic reception. Gates recommended him for a brigadier-general's commission for services which another actually performed, and succeeded in gaining it, but their friendship was broken by the collapse of the Conway Cabal against George Washington in which both were implicated and about which Wilkinson had indiscreetly blabbed. Wilkinson then resigned (March 1778) his newly-acquired commission, but later rejoined the service in the quartermaster-general's department, and was clothier-general from July 1779 to March 1781.

In common with many other army officers Wilkinson now turned toward the West, and in 1784 settled near the Falls of the Ohio (Louisville), where he speedily became a prominent merchant and farmer and a man of considerable influence. He began to take an active part in the movement for separate statehood for Kentucky, and in 1787 he entered into an irregular commercial agreement with the Spanish officials of Louisiana. At this time, as his own papers in the Spanish archives show, he took an oath of allegiance to Spain and began to intrigue with his fellow Kentuckians to detach the western settlements from the Union and bring them under the influence of the Louisiana authorities. His commercial connections at New Orleans enabled him to hold out the lure of a ready market at that port for Kentucky products, and this added greatly to the strength of the separatist movement. He neutralized the intrigues of certain British agents who were then working in Kentucky. For these various services he received until 1800 a substantial pension from the Spanish authorities, being officially known in their correspondence as "Number Thirteen." At the same time he worked actively against the Spanish authorities, especially through Philip Nolan. Wilkinson's ventures were not as lucrative as he hoped for, and in October 1791 he was given a Lt. Col.'s commission in the regular army, possibly, as a contemporary suggested, to keep him out of mischief. During this year he took an active part in the minor campaigns which preceded General Arthur St. Clair's disastrous defeat by the Indians. As brigadier-general (from March 1792) and second in command, he served under General Anthony Wayne in the latter's successful campaign of 1794 against the Indians, and in this campaign he seems to have tried to arouse discontent against his superior among the Kentucky troops, and to have intrigued to supplant him upon the reduction of the army. Upon Wayne's death in 1796, Wilkinson became general in command of the regular army, retaining his rank as brigadier and likewise his Spanish pension. He seems to have tried to stir up both the Indians and the Spaniards to prevent the survey of the southern boundary of the United States in 1797 and 1798, and succeeded in delaying Commissioner Andrew Ellicott for several months in this important task. At the same time his protege, the filibusterer, Philip Nolan, was engaged in a reconnaissance for him west of the Mississippi. In 1803 Wilkinson was one of the commissioners to receive Louisiana from France, and in 1805 became governor of that portion of the Louisiana Purchase above the 33rd parallel, with headquarters at St. Louis.

In his double capacity as governor of the Territory and commanding officer of the army, reasonably certain of his hold on Thomas Jefferson, and favorably situated upon the frontier remote from the center of government, he attempted to realize his ambition to conquer Mexico. For this purpose in 1805 he entered into an agreement with Aaron Burr, and in 1806 sent Zebulon Pike to explore the most favorable route for the conquest of the Southwest. Before his agent returned, however, he had betrayed his colleague's plans to Jefferson, formed the Neutral Ground Agreement with the Spanish commander of the Texas frontier, placed New Orleans under martial law, and apprehended Burr and some of his alleged accomplices. In the ensuing trial at Richmond the prisoners were released for lack of sufficient evidence to convict, and Wilkinson himself emerged with a much damaged reputation. He was then subjected to a series of courts-martial and congressional investigations, but succeeded so well in hiding traces of his duplicity that at the start of the War of 1812 he resumed his military command at New Orleans, and in 1813 was promoted major general and took possession of Mobile. Later in this year he made a most miserable fiasco of the campaign against Montreal, and this finally brought his military career to a dishonorable end. For a time he lived upon his plantation near New Orleans, but later appeared in Mexico City as an applicant for a land grant, incidentally acting as agent for the American Bible Society. Here on the 28th of December 1825 he succumbed to the combined effects of climate and of opium.